Non-Hodgkin’s lymphoma (NHL) is a diverse family of cancers that affect a part of the body’s immune system known as the lymphatic system. In NHL white blood cells become cancerous and develop into tumors at key points in the lymphatic system known as the lymph nodes, before spreading to other tissues. About 50,000 Americans develop NHL every year, and while effective treatments such as Rituximab are available they don’t work for all patients and every year NHL kills nearly 20,000 people in the USA.
So it’s not surprising that the news that Blinatumomab, a novel treatment developed by the German firm Micromet, has performed very well in early clinical trials has been greeted with enthusiasm by cancer research charities and the stock market alike.
In the trials (1) published this week in the prestigious journal Science, Blinatumomab was given to 38 NHL patients who had not responded to other treatments. In 7 of these patients tumors were found to have shrunk dramatically while in 4 patients the tumors disappeared completely. Blinatumomab is the first BiTE antibody to enter clinical trials, and its innovative design combines a portion of an antibody, a protein produced by the immune system that binds to foreign material in the body, that targets the cancer cell with a portion of an antibody that binds to the T-cells of the immune system. The BiTE antibody directs the T-cell to the cancer cell, which the T-cell then destroys. Blinatumomab was developed after earlier studies using animal models of NHL had shown that antibodies could direct T-cells to target cancer cells, and it was hoped that the BiTE antibodies would do this more effectively. Of course before it was assessed in human clinical trials the BiTE antibody Blinatumomab was studied in mouse models of NHL, since it was important to determine that they could target circulating immune cells to the tumors (2).
The contribution of animal research to the development of Blinatumomab was not limited to the evaluation of anti-cancer activity and pre-clinical safety, it was also crucial to manufacturing Blinatumomab itself*. BiTE antibodies are produced by heavily modifying a type of antibody known as a monoclonal antibody that binds very specifically to a particular target in the body. The first step of monoclonal antibody production is the immunization of an animal, usually a rodent, with the protein such as a cancer cell protein to which you wish the antibody to bind. Animals are required for this step because an immune system is needed to produce the immune cells that recognize the target protein, and humans cannot be used for this process both because they cannot be injected with a disease-bearing agent in order to make antibodies, and because the human body does not produce antibodies to the human proteins that researchers often wish to target. Blood samples containing cells that produce antibodies against the foreign protein are then taken from the animal. These antibody producing cells are fused with a special cancer cell to produce a hybrid cell, or hybridoma, which can be grown almost indefinately in the petri dish and produce a large supply of monoclonal antibodies. These monoclonal antibodies can then in their turn be modified to produce antibody derived drugs such as Rituximab and Blinatumomab.
We hope that larger trials of Blinatumomab against NHL confirm the results of this early trial, and that it will go on to be a valuable addition to the range of treatments available to fight this deadly disease.
* While hybridoma based monoclonal antibody production methods have been very successful, and are vital to current efforts to develop antibody based medicines, replacement technologies that require far fewer animals are currently being developed. In the coming decades it is hoped that hybridoma based methods will increasingly be replaced by improving in vitro technologies, for example antibody phage libraries that display vast numbers of human or animal antibody fragments and can be used to identify antibodies specific for a particular target. This is a good example of the 3Rs in practise.
Paul Browne
1) Bargou R. et al. “Tumor regression in cancer patients by very low doses of a T cell-engaging antibody.” Science Volume 321(5891), pages 974-977 (2008).
2) Dreier T. et al. “T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct.” J. Immunol. Volume 170(8), pages 4397-4402 (2003)
Speaking of Research 
Looking over this article I noticed that I was a little too enthusiastic with my editing, so here’s a little more detail on the animal research described in the 2003 paper by Dreier T. et al.
In the study they used an immunodeficient mouse known as the Nod/Scid mouse which was first developed in the mid 1990’s. Because the Nod/Scid lacks its own immune system cells from the human immune system can be introduced into the mouse and studied, and recently an almost intact human immune system has been reconstituted in the mouse which may be very useful for studying HIV http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050013.
In the study by Dreier and colleagues human immune cells and cancer cells were mixed together and injected into the NOD/SCID mice. This was important since it allowed them to study a BiTE antibody that was specific for two human targets. Several days later the mice were injected with either Blinatumomab or a control and the effect on tumour growth and survival was observed. The purpose of this was to assess whether the injected BiTE antibody could travel through the body and target a sufficient number of T-cells to the cancer cells to prevent tumour growth. The study showed that Blinatumomab, but not the control, could indeed stimulate T-cells to attack the cancer cells and block tumour growth.